Lessons from Familial Cancers
By Gloria M. Petersen, Ph.D.

The creation last year of the Cancer Genetics Network by the National Cancer Institute is an extraordinary response to the rapid series of cancer gene discoveries and their translation into clinical practice. All of these events have occurred only in the past decade. It would be useful at this time for us to pause and appreciate some important lessons that familial cancers have taught us.

1. Genetic susceptibility to cancer is a fact. While there has been plenty of evidence that the environment and lifestyle are culprits in cancer causation, it has also been suspected that there are individual differences in our genetic blueprints that make us more predisposed (or resistant) to cancer. Until the availability of molecular and genetic research tools, this suspicion was difficult to prove. We now know that a substantial proportion of people who have developed cancer may have been genetically susceptible. Decades of research up to the molecular era showed a consistent pattern for many cancers (breast cancer, colon cancer, lung cancer, pancreas cancer, melanoma, prostate cancer). There are patterns of familial clustering, even after controlling for environmental exposures. That is, close blood relatives of patients with cancer were themselves at increased risk for cancer. In some cases, if the patient developed cancer at an age that was younger than the average age at which the cancer generally occurred, the risk to relatives might even be higher.

Astute clinical insights into the types of cancers that clustered in families were an important contribution. For example, the observation that colon cancer, endometrial cancer, small bowel cancer, ovarian cancer, and ureteral cancer could cluster in families (hereditary nonpolyposis colorectal cancer syndrome, or HNPCC), or that sarcoma, breast, leukemia, and lung cancer clustered in others (Li-Fraumeni syndrome) led to improved identification of study families. The study of cancer family clusters, in turn, has led to the discovery of several dozen different cancer genes. If a person carries a mutation in one of these cancer genes, they are at significantly higher risk of developing cancer.

2. Cancer susceptibility genes have given us important new insights into how cancer can develop. Gene discoveries using cancer families in research has led to a new understanding of how genetic alterations can lead a cell to become malignant. Two mechanisms were discovered through the study of cancer family syndromes:

Our current understanding of tumor suppressor genes is the result of research on a rare hereditary eye cancer, retinoblastoma. The combined insights of clinicians, statisticians, geneticists, and molecular biologists resulted in a revolution of thinking about cancer gene action. Until the retinoblastoma gene, RB1, was discovered, it was presumed that cancer genes acted as accelerators of tumor growth (oncogenes). The retinoblastoma research showed that there were also genes that normally act as brakes on cell growth. When these genes are altered (mutated or deleted), then tumor growth will not be halted. Some of the terms that we use in cancer genetic research today, such as "two-hit model" (two genetic "hits" or mutations can result in cancer) and "loss of heterozygosity" (the genotype of a tumor cell is molecularly altered from the constitutional genotype of the same individual), were coined to describe how RB1 and other tumor suppressor genes act.

Similarly, the discovery of a new mechanism by which persons may be susceptible to cancer, DNA mismatch repair defects, is the result of research on one of the more common forms of inherited colorectal cancer, HNPCC. It was found that the DNA of tumors of patients with HNPCC are altered from their constitutional pattern (known as DNA microsatellite instability). It was also observed that HNPCC families had mutations in genes that control the way that DNA repairs itself during cell division. Taken together, these findings have opened a new avenue for research into how cancer can arise in susceptible persons. The value of DNA microsatellite instability as a tumor test is now being validated and may result soon in a diagnostic and prognostic tool.

3. Increasingly, persons in cancer families can better learn their cancer risk, and have more options for screening and cancer prevention. With the identification of specific cancer predisposing mutations that occur in cancer families, it has become feasible to use such information in the clinic setting, both to confirm diagnoses of cancer family syndromes, and to provide options for presymptomatic gene testing in at-risk family members. Genetic testing is a new technology that is available to improve risk assessment by identifying those at high genetic risk. At the same time, ongoing research is enabling health care providers to target appropriate screening and management recommendations in cancer families. At present, genetic testing is available for several hereditary cancers, such as BRCA1 and BRCA2 for hereditary breast-ovarian cancer, APC, hMSH2, and hMLH1 for hereditary colon cancers, and p53 for Li-Fraumeni syndrome. Research on screening intervals, types of surveillance and prophylactic surgery options, and in the future, chemoprevention strategies will enhance efforts to prevent cancer. The involvement of cancer families in genetic testing research has been invaluable in helping clinicians to develop the most appropriate and useful ways to deliver this developing clinical service. In conclusion, the advances in our understanding of cancer genetics have been dramatic, and the lessons that cancer families have taught us continue to unfold.

Dr. Petersen is the Principal Investigator of the Mid-Atlantic Cancer Genetics Network. She is an Associate Professor in the Human Genetics Program of the Department of Epidemiology at The Johns Hopkins School of Public Health in Baltimore, MD.